Biallelic Mutations Causing Rare Pediatric Brain Disorder VARS

MARCH 12, 2019

Rachel Lutz

Researchers now know the cause of VARS, a rare pediatric brain disorder, according to a new report.

Investigators from McGill University Health Centre and Rady’s Children’s Institute for Genomic Medicine studied 7 patients from 5 unrelated families in order to further examine their different biallelic missense variants in VARS. The study authors explained that patients often present with a “range of global developmental delay, epileptic encephalopathy, and primary or progressive microcephaly.”

These children showed epileptic seizures and other abnormalities on their brain MRI scans. Additionally, the investigators performed genetic testing on blood samples from the patients, who had neurodevelopment disabilities and were from San Diego, Montreal, and Cairo. By doing so, they discovered the VARS gene mutations, which had not been previously associated with human disease, the investigators explained.

Study co-author Jennifer Friedman, MD, a neuroscientist with the Rady Children’s Institute for Genomic Medicine told Rare Disease Report that at first, despite genomic sequencing, there was no diagnosis for the Rady Children’s Hospital patient.

“Though the VARS variants were identified by our team, there was insufficient evidence in the literature to conclude these were the cause of the child’s neurologic symptoms,” she said. “Cooperation among multiple other clinicians, who similarly had identified VARS variants in their patients was necessary to prove the disease-causing effects of these mutations. Teamwork across multiple clinical and research groups around the world is what ultimately enabled conclusively linking disruption of VARS to these children’s conditions.”

None of the investigators’ patients survived past childhood, they said. “Most succumb from medical complications in the first few years of life, suggesting a lethal condition,” the study authors wrote.

Without any treatment for this condition, the results of the study are the first step in designing targeted therapies, the study authors said.

The amino acid valine is necessary for cellular health, they said, but in these patients, a genetic mutation disrupted a protein’s ability to generate valine. With this in mind, the study authors believe that the children could eventually use treatment that supports the synthesis of new valine in their brains.

“This study confirms the association of VARS mutation with developmental delay and epilepsy and will allow other children who carry mutations in the VARS gene to be diagnosed,” Friedman said. “These findings will enable families with children with this condition to learn what is making their child sick. In addition, this work sets the stage for development of therapies that physicians may be able to use for treatment of this and related conditions in the future.”

The investigators next want to find out whether dietary supplementation with valine or gene therapy can help restore the mutated protein in the brain of these patients.

“For now, the main change to clinical practice, is that physicians may consider VARS gene mutation as a possible diagnosis when evaluating children with developmental delays, small head size or epilepsy,” Friedman concluded.” In the future there is hope that this finding may lead to development of targeted therapies for these children.”